The goal of this proposal is to increase our understanding of the process of pancreatic islet cell growth and regeneration. This study is extremely important because in humans with Insulin Dependent Diabetes Mellitus (IDDM) the pancreatic islet cells are lost from an autoimmune attack, with no possibility of being regained. Individuals do not have the ability to regenerate their islets. In this proposal we seek to determine whether islet cell regeneration could be induced in adults, curing this devastating disease. For this purpose we have been studying a unique cytokine transgenic model where the pancreatic islets regenerate continuously from proliferating duct epithelial progenitor cells. The study of the regulation and the mechanism of the regeneration process in this important model will allow a full understanding of, and the ability to manipulate this process. In this proposal we test the hypothesis that an important governing mechanism for islet regrowth is that the cytokine immortalizes islet progenitor cells in the fetal pancreas, facilitating their population of the adult pancreas. Secondly, we test the hypothesis derived from progress during the previous funding period: that growth factors are critical for the observed proliferative effects. Thirdly, we test the hypothesis that the reason no regeneration occurs in IDDM is that the appropriate trophic factors are missing but can be replaced. Lastly, we propose experiments aimed at identifying the stem cell from which the islets arise. The information gained from these experiments should allow us to approach therapy of IDDM in experimental models and in humans by stimulating the differentiation of islet progenitor cells.